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Limits of mouse models for human diseases

Due to ethical concerns, we pursue many experiments relevant to human health …

How well does the mouse act as a model for humans? Researchers often explore human diseases using mice, because they have a short generation time and convenient methods for altering or eliminating genes. But mice clearly aren't humans, and there are often nagging questions about how much working in mice, especially mice kept in the simple, sterile environment of the lab, can tell us about a human. A paper that will be released in PNAS takes a look at this question from the perspective of mutations, and finds that there may be some significant limits to what we can compare.

The researchers used the NCBI's Online Mendelian Inheritance in Man database to identify over 1,700 cases where there was a clear link between a single human gene and a disease phenotype. They then started narrowing this list down, throwing out genes which lack a clear single-gene equivalent in mice (leaving 1,450), ignoring those where a mutant in mice hasn't been described (750), and then clearing out those that were not clear loss-of-function mutations. By the time the researchers were done, the data set had only 120 human genes in it, all of which caused lethality pre-puberty or sterility in adults.

Now, there's a clear problem here, in that many mutations in mice cause lethality prior to birth, a condition we're unlikely to be able to deal with in human genetics. So, the analysis has to be considered severely limited in this regard. With that caveat out of the way, the authors did excellent work with the limited data set they had.

The big surprise was that over 20 percent of these essential genes in humans were nonessential in mice, meaning the mice lived long enough to breed. The authors used gene expression databases to determine whether the difference might arise from changes in where the gene is produced, but that search came up empty. So they tracked evolution of the protein sequence, using five additional species to see if and where the proteins were changing. This showed not only that there were signs of positive selection in the protein sequences, but that most of these changes took place within the primate lineage.

So, although I don't think general conclusions about human/mouse differences can be reached based on the small data set, it does appear that the authors have stumbled onto a significant effect within it. They note that the genes within this set are unusually enriched in those that control the metabolism of waste within a cell, and speculate that this may be related to the extended lifespans of primates relative to other mammals. Given that we have a draft genome for the elephant, that speculation should be easily testable.